|
|
Estimated life expectancy >+3 months Recovery from toxic effects of prior therapy to NCI |
|
|
|
|
|
CTCAE v5.0 Grade 1 (non-hematologic toxicities) or Grade <=2(hematologic toxicities, except |
|
|
|
|
|
deep vein thrombosis) KPS >=70% |
|
|
|
|
|
Adequate organ function as determined by |
|
|
|
|
|
Absolute Neutrophil ≥1500/microliter (may not use G-CSF or GM CSF) |
|
|
|
|
|
Platelet ≥100 × 103/microliter |
|
|
|
|
|
Hemoglobin ≥9 g/dL (may not transfuse or use erythropoietin to obtain this Hgb level) |
|
|
|
|
|
Creatinine Clearance ≥ 40ml/min (Cockcroft-Gault) |
|
|
|
|
|
Total bilirubin ≤1.5 times ULN (or ≤ 2 times ULN for patients with known Gilbert's |
|
|
|
|
|
syndrome) |
|
|
|
|
|
AST ≤ 3 times ULN |
|
|
|
|
|
ALT ≤ 3 times ULN |
|
|
|
|
|
INR, PT, PTT, or aPTT ≤1.5 x ULN Note: The use of anticoagulants is permitted as long |
|
|
|
|
|
as the PT/(a)PTT is within therapeutic limits (according to the local institution |
|
|
|
|
|
standard) and the patient has been on a stable anticoagulant regimen for at least 2 |
|
|
|
|
|
weeks prior to study Day 1 |
|
|
|
|
|
If on antiepileptic drug; dose must be stable and no seizures 14 days prior to study Day 1 |
|
|
|
|
|
If on corticosteroids at baseline, dose must be stable or decreasing for at least 5 days |
|
|
|
|
|
prior to study Day 1. For the dose expansion part of the study, the dose must be ≤ 4 mg |
|
|
|
|
|
dexamethasone per day (or equivalent dose if other corticosteroids are used). A higher |
|
|
|
|
|
stable dose of corticosteroids, if used as HRT, may be allowed upon discussion with the |
|
|
|
|
|
Females of childbearing potential must have a negative serum or urine pregnancy test Male |
|
|
|
|
|
Medical Monitor |
|
|
|
|
|
or female patients of child-producing potential must agree to use contraception or use |
|
|
|
|
|
prevention of pregnancy measures or agreement to refrain completely from heterosexual |
|
|
|
|
|
intercourse during the study and for 6 months (females & males) after the last dose of |
|
|
|
|
|
study drug |
|
|
|
|
|
Prior therapy with bevacizumab or other anti-vascular endothelial growth factor (VEGF)
|
|
|
|
|
|
treatments within 3 months prior to study Day 1, Multifocal disease, leptomeningeal
|
|
|
|
|
|
metastasis, or extracranial metastasis Abnormal ECGs that are clinically significant
|
|
|
|
|
|
including those where QT prolongation (QTcF>450 msec for males and >470 msec for females)
|
|
|
|
|
|
and/or history of Torsade de Pointes Left ventricular ejection fraction <40% as determined
|
|
|
|
|
|
by ECHO or MUGA Known dysphagia, short-gut syndrome, gastroparesis, or other conditions
|
|
|
|
|
|
that limit the ingestion or gastrointestinal absorption of drugs administered orally Know
|
|
|
|
|
|
active Chrohn's or other inflammatory bowel disease History of another primary cancer
|
|
|
|
|
|
within the 2 years prior to study Day 1, except for the following: nonmelamona skin cancer
|
|
|
|
|
|
A known active acute or chronic infection including, but not limited to, HIV, HBV, and HCV
|
|
|
|
|
|
cervical carcinoma in situ, superficial bladder cancer that has been removed or curatively
|
|
|
|
|
|
treated
|
|
|
|
|
|
[Patients who have completed a course of anti-viral treatment for HVC are eligible provided
|
|
|
|
|
|
The presence of any active retinal abnormality determined by screening tests using visual
|
|
|
|
|
|
than an HCV polymerase chain reaction shows no detectable virus] Pregnant or breastfeeding
|
|
|
|
|
|
acuity, visual field, fundoscopy, and OCT Significant cardiovascular disease, including
|
|
|
|
|
|
[Note: Female breastfeeding patients may be enrolled if they interrupt breastfeeding
|
|
|
|
|
|
NYHA Class III or IV congestive heart failure, myocardial infarction, unstable angina
|
|
|
|
|
|
Breastfeeding should not be resumed for at least 6 months after the last dose of study
|
|
|
|
|
|
poorly controlled cardiac arrhythmias, or stroke in the preceding 6 months prior to study
|
|
|
|
|
|
drug
|
|
|
|
|
|
illness/social situations that would limit compliance with study requirements, or disorders
|
|
|
|
|
|
associated with significant immunocompromised state Major surgical procedure, surgical
|
|
|
|
|
|
resection, open biopsy, or significant traumatic injury within 4 weeks prior to study Day 1
|
|
|
|
|
|
or anticipation of need for major surgical procedure during the course of the study Minor
|
|
|
|
|
|
Day 1 Uncontrolled intercurrent illness including, but not limited to, psychiatric
|
|
|
|
|
|
surgical procedures, fine needle aspirations, or core biopsies within 7 days prior to study
|
|
|
|
|
|
Day 1 Evidence of CNS hemorrhage on baseline MRI or CT scan (except for postsurgical
|
|
|
|
|
|
asymptomatic, Gr 1 hemorrhage that has been stable at least 4 weeks for enrolled patients)
|
|
|
|
|
|
Chemotherapy or investigational anticancer therapy administered within 4 weeks (except 6
|
|
|
|
|
|
weeks for nitrosoureas and immunotherapy, or 8 weeks for an implanted nitrosoureas wafer)
|
|
|
|
|
|
prior to study Day 1 Radiotherapy within 12 weeks prior to study Day 1, unless relapse is
|
|
|
|
|
|
confirmed by tumor biopsy or new lesion outside of radiation field, or if there are 2 MRIs
|
|
|
|
|
|
(performed 8 weeks apart) confirming progressive disease Concurrent use of prohibited
|
|
|
|
|
|
medications: methylprednisolone, prednisone, carbamazepine, phenytoin, phenobarbital, and
|
|
|
|
|
|
other strong or moderate CYP3A4 inhibitors or inducers, and strong CYP2D6 inhibitors. These
|
|
|
|
|
|
should be discontinued 1 week or 5 half-lives (whichever is greater) prior to study Day 1
|
|
|
|
|
|
Concurrent treatment with Tumor Treatment Field (Optune) is not allowed. Patients must stop
|
|
|
|
|
|
Optune 1 day prior to the first dose of study drug. Any wounds from Optune must be healed
|
|
|
|
|
|
Any other lung condition that in the investigators' judgement may put the patient at
|
|
|
|
|
|
History of, within 6 months of study Day 1
|
|
|
|
|
|
an increased risk for lung toxicity (including, but not limited to, suspected
|
|
|
|
|
|
adequately prior to study Day 1
|
|
|
|
|
|
Pneumonitis or interstitial lung disease
|
|
|
|
|
|
interstitial lung disease or radiation-induced lung injury)
|
|
|
|